BETHESDA, MD – A new study involving federal medicine researchers raised the question of whether small cell lung cancer (SCLC) is an inherited predisposition. The answer is important because it opens the possibility of using targeted therapies based on the genes involved.
“Because tobacco is a potent carcinogen, secondary causes of lung cancer are often diminished in perceived importance,” explained researchers from Walter Reed National Military Medical Center and the National Cancer Institute.
An editor’s summary added, “Small cell lung cancer (SCLC) is generally regarded as a smoker’s cancer. However, the genetic factors that affect susceptibility to SCLC have not been fully evaluated.”
In response, the study team sought to assess the extent of inherited susceptibility to SCLC, which is the most lethal type of lung cancer. To do that, investigators sequenced germline exomes of 87 patients — 77 SCLC and 10 extrapulmonary small cell — and considered 607 genes; they identified 42 deleterious variants in 35 cancer-predisposition genes among 43.7% of patients. Their findings, published in Science Translational Medicine, then were validated in an independent cohort of 79 patients with SCLC.1
The authors reported that loss of heterozygosity was observed in 3 of 14 (21.4%) tumors. In 10.3% of patients, identification of variants influenced medical management and family member testing, they added.
“Unselected patients with SCLC were more likely to carry germline RAD51 paralog D (RAD51D), checkpoint kinase 1 (CHEK1), breast cancer 2 (BRCA2), and mutY DNA glycosylase (MUTYH) pathogenic variants than healthy controls,” the study pointed out.
Researchers determined that germline genotype was significantly associated with the likelihood of a first-degree relative with cancer or lung cancer (odds ratio: 1.82, P = 0.008; and 2.60, P = 0.028), and longer recurrence-free survival after platinum-based chemotherapy (P = 0.002), independent of known prognostic factors.
“Treatment of a patient with relapsed SCLC and germline pathogenic mutation of BRCA1 interacting protein C-terminal helicase 1 (BRIP1), a homologous recombination-related gene, using agents synthetically lethal with homologous recombination deficiency, resulted in a notable disease response,” the authors wrote, adding, “This work demonstrates that SCLC, currently thought to result almost exclusively from tobacco exposure, may have an inherited predisposition and lays the groundwork for targeted therapies based on the genes involved.”
- Tlemsani C, Takahashi N, Pongor L, Rajapakse VN, et. Al. Whole-exome sequencing reveals germline-mutated small cell lung cancer subtype with favorable response to DNA repair-targeted therapies. Sci Transl Med. 2021 Jan 27;13(578):eabc7488. doi: 10.1126/scitranslmed.abc7488. PMID: 33504652.